RNAi Reveals Phase-Specific Global Regulators of Human Somatic Cell Reprogramming | Zendy

Cheng-Xu Delon Toh | Zendy; J. Chan | Zendy; ZhengShan Chong | Zendy; Haofei Wang | Zendy; Hongchao Guo | Zendy; Sandeep Satapathy | Zendy; Dongrui Ma | Zendy; Germaine Goh | Zendy; Ekta Khattar | Zendy; Yang Lin | Zendy; Vinay Tergaonkar | Zendy; YoungTae Chang | Zendy; James J. Collins | Zendy; George Q. Daley | Zendy; Keng Boon Wee | Zendy; Chadi El Farran | Zendy; Hu Li | Zendy; Yoon-Pin Lim | Zendy; Frédéric Bard | Zendy; YuinHan Loh | Zendy

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RNAi Reveals Phase-Specific Global Regulators of Human Somatic Cell Reprogramming

Author(s) -

Cheng-Xu Delon Toh,

J. Chan,

ZhengShan Chong,

Haofei Wang,

Hongchao Guo,

Sandeep Satapathy,

Dongrui Ma,

Germaine Goh,

Ekta Khattar,

Yang Lin,

Vinay Tergaonkar,

YoungTae Chang,

James J. Collins,

George Q. Daley,

Keng Boon Wee,

Chadi El Farran,

Hu Li,

Yoon-Pin Lim,

Frédéric Bard,

YuinHan Loh

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.05.049

Subject(s) - reprogramming , biology , chromatin , rna interference , rna splicing , gene knockdown , effector , microbiology and biotechnology , epigenetics , epigenome , repressor , genetics , rna , computational biology , gene , transcription factor , gene expression , dna methylation

Incomplete knowledge of the mechanisms at work continues to hamper efforts to maximize reprogramming efficiency. Here, we present a systematic genome-wide RNAi screen to determine the global regulators during the early stages of human reprogramming. Our screen identifies functional repressors and effectors that act to impede or promote the reprogramming process. Repressors and effectors form close interacting networks in pathways, including RNA processing, G protein signaling, protein ubiquitination, and chromatin modification. Combinatorial knockdown of five repressors (SMAD3, ZMYM2, SFRS11, SAE1, and ESET) synergistically resulted in ∼85% TRA-1-60-positive cells. Removal of the novel splicing factor SFRS11 during reprogramming is accompanied by rapid acquisition of pluripotency-specific spliced forms. Mechanistically, SFRS11 regulates exon skipping and mutually exclusive splicing of transcripts in genes involved in cell differentiation, mRNA splicing, and chromatin modification. Our study provides insights into the reprogramming process, which comprises comprehensive and multi-layered transcriptional, splicing, and epigenetic machineries.

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